The basic of this proposed research arises from the observation of the behavioral central nervous system depressant activity of gamma-hydroxybutyrate (GHB) demonstrated in a number of animal species, including man; the observation of an NADPH-coupled dehydrogenase in mammalian brain involved in the conversion of succinic semialdehyde to GHB; the demonstration of the endogenous occurrence of GHB in rat, guinea pig, cat, bovine and human brain and the observation that exogenously administered GHB produces a marked and selective increase in striatal dopamine in the rat as a result of its ability to produce a reversible lesion of the dopamine neurons in the nigro-neostriatal pathway. Thus normal mammalian brain contains and is capable of forming an endogenous compound which when administered systemically produces behavioral depression and an interruption of impulse flow in dopaminergic neurons. It is our aim to establish the natural occurrence of BHG in human and monkey brain by GLC-mass spectrometry; to determine its regional distribution; to determine the endogenous levels and regional distribution of GHB in postmortem brain obtained from patients with neurological and psychiatric disorders; to study the metabolic routes for synthesis and degradation of GHB; to try to determine the functional role this compound plays in the central nervous system; to investigate the mechanism by which GHB ultimately causes a suppression of impulse flow in the nigro-neostriatal pathway and to examine the structural requirements for this effect; to determine the mechanism responsible for the activation of tyrosine hydroxylase resulting from an abolition of impulse flow in the dopaminergic pathway due to pharmacological treatment with GHB or mechanical interruption of this pathway; to investigate if all dopaminergic neurons respond in a similar fashion to the systemic administration of GHB or to blockade of impulse flow by other means; and finally to learn more about the biochemical organization, regulatory control and potential sites for drug interaction with monoaminergic neurons in the central nervous system.